This program project is designed to mount a multidisciplinary study of the interplay among dopaminergic, cholinergic and other neutrotransmitter system in the basal ganglia and in other brain regions, and to determine the effects that alterations in these systems have on extrapyramidal motor function and behavior. Chronic administration of neuroleptic drugs is known to result in aberrant motor behavior, most notably, tardive dyskinesia. This may be an example of neuronal plasticity, whereby the neural systems respond to chronic inhibition by developing an enhanced sensitivity to agonists. The effects of acute and chronic administration of psychoactive agents, and other manipulations directed at modifying input to the basal ganglia, on the activity of neurotransmitter biosynthetic enzyme, the modulation of neurally mediated catecholamine release, the electrophysiological responses of caudate neurons, the sensitivities and densities of neurotransmitter receptors in caudate and alteration in tissue adenylate cyclase, cyclic nucleotides, protein kinases and phosphorylation of specific proteins will be evaluated. Attempts will be mad to measure dopamine and homovanillic acid release from the striatum in vivo and the effects of neuroleptic and other drugs on this process. The role of glial cells in the maintenance and development of catecholamine and other neurons in culture will be evaluated. The influence of calcium dependent regulator protein and membrane glycoproteins and glycolipids on axonal sprouting in culture will be investigated. The relationship between the levels of biogenic amine metabolites in ventricular fluid and in urine of monkeys will be assessed during the following administration of neuroleptic drugs and levodopa. Attempts will be made to assess the role of a neurotoxic metabolite of dopamine in the pathogenesis of extrapyramidal disturbances associated with levodopa administration. Clinical studies directed toward predicting susceptibility to tardive dyskinesias with prolonged neuroleptic therapy will be performed. The relationship between spontaneous activity and evoked responses in the electroencephalogram, excretion of dopamine metbolites and the development of tardive dyskinesias in man will be studied.